Medullary Thyroid Carcinoma (MTC) is a rare malignancy originating from the calcitonin-secreting C cells of the thyroid. Unlike its much more common counterpart, papillary thyroid carcinoma, there is currently no known cure for metastatic MTC, which is not radioiodine avid. Common sites of metastases include the lungs, liver and bones. Among other factors, prognosis depends on disease stage and tumor growth rate, as monitored by the doubling times of serum tumor markers calcitonin and carcinoembryonic antigen (CEA). For patients with distant metastases, the 10 year survival rate is estimated to be 20-40%.
There is no effective adjuvant therapy for early stage MTC, which is commonly resistant to traditional cytotoxic chemotherapy regimens due to slow cytokinetic growth and intrinsic molecular factors, which inhibit apoptosis. Currently available systemic therapies for MTC produce only partial and transient responses, and are limited to use in patients with advanced or rapidly progressing disease. There are currently two FDA-approved targeted molecular therapies for MTC, the multi-kinase inhibitors vandetanib and cabozantinib. In Phase III clinical trials, both drugs improved progression-free survival, but failed to significantly extend overall survival. In fact, for patients lacking RET mutations, cabozantinib reduced median survival by several months. In the hundreds of patients treated in both trials, there were no documented complete responses and investigators deemed several fatalities to be treatment related. The vast majority of patients experienced grade 3 or grade 4 adverse events, including diarrhea, hypertension, desquamation, fatigue and fistulas. Due to harsh side effects, clinical use of both drugs is generally limited to patients with advanced and symptomatic disease. As current treatment regimens are inadequate and impact quality of life, there is a significant unmet clinical need for novel therapies to treat metastatic MTC.